Pleiotropic Effects of Atorvastatin in High Cardiovascular Risk Patients

Summary

The present study constitutes a study examining the effect of atorvastatin on vascular
function in high cardiovascular risk patients. For this purpose the investigators will
record atorvastatin effects on statin-naïve patients (patients that start statins treatment
for first time). More specifically the investigators will study atorvastatin effects on:

In this arm patients with ischemic heart failure (NYHA II-III) will be recruited. In a
double-blind crossover design heart failure patients (n=30) naïve to statins treatment will
be randomized to atorvastatin 10mg/day (n=15) or 40mg/day (n=15) for 4 weeks. At the end of
4 weeks a 2-week wash out period will follow and then all patients will switch atorvastatin
dose (e.g all patients that were under atorvastatin 10mg/day will be switched to 40mg/day
and vice versa).

Both at baseline and at the end of 4 weeks period patients will undergo

- blood sampling

- assessment of endothelium-dependent and -independent vasodilatation and

- vascular elastic properties study (see below for methods).

ARM B

In this arm, patients undergoing cardiac surgery (CABG, valve replacement or aortic surgery)
that are not under statins treatment will be recruited (n=100). Patients will be randomized
in a double-blind fashion to atorvastatin 40mg/day or placebo for 3 days before surgery.

Both at baseline and on surgery day patients will undergo

- blood sampling and

- assessment of endothelium-dependent and -independent vasodilatation (see below for
methods) while

- during surgery tissue samples (grafts, myocardium and adipose tissue segments) will be
obtained that will be used for ex-vivo studies (see below).

Consent form

Every patient participating in the clinical study will give a written consent form, and will
be informed in details for the aims of the study by the researchers. During recruitment
process all participants will fill out a questionnaire with demographic and clinical data.
All information given by the participants will be held highly classified. All participants
will give written consent for the programmed biochemical measurements and vascular studies,
as stated in the study design. Specifically for patients undergoing cardiac surgery (arm B)
an additional consent form will be filled out that will permit grafts, myocardium and
adipose tissue segments harvesting during cardiac surgery.

Methods

Endothelial-dependent and independent vasodilatation: Brachial Artery Flow-Mediated
Dilatation (FMD) of the brachial artery will be measured as a quantitative readout of
NO-mediated conduit vessel endothelial function, as we have done in several previous studies
and in accordance with international guidelines.Endothelial dependent (hyperaemic flow after
cuff occlusion) and endothelial independent (GTN) responses of the brachial artery will be
measured using high-resolution ultrasound imaging with automated vessel diameter
measurements (Vascular Analyser, MIA Inc. Iowa). FMD and GTN induced dilatation will be
measured as absolute and proportional changes in arterial diameter.Reproducibility data from
our laboratory show a coefficient of variation for inter-study measurements of <10%
comparable to other reports.

Arterial Stiffness: Measures of central arterial stiffness are independent predictors of
cardiovascular outcomes in large prospective studies and is inversely correlated with
measures of endothelial function.Arterial tonometry is a simple, reproducible method to
measure, non-invasively, arterial stiffness. We have already established measures of central
aortic stiffness - augmentation index and aortic pulse wave velocity - using the Sphygmocor
system for applanation tonometry (AtCor Medical, Australia). Mathematical transformation of
the radial pulse waveform is used to derive the augmentation index.The difference in time
for the pulse waveform to reach the carotid compared to the femoral artery measures pulse
wave velocity down the aorta, with faster transit associated with a 'stiffer' aorta.

Systemic oxidative stress: We will study statins effects on systemic oxidative stress using
a systemic oxidative stress marker like lipid peroxides. In more details lipid peroxides
will be quantified in patients' plasma using malondialdehyde assay (ΜDA-TBARS).

Vascular oxidative stress: ROS generation in the vascular segments obtained during CABG will
be determined by lucigenin-enhanced chemiluminescence. The same measurements will also be
performed in myocardium segments obtained during CABG form the site of right atrium
incision, where extracorporeal circulation cannula is inserted. Our aim is to determine
statins effects on vascular and myocardial ROS generation.

Adipose tissue cultures: During cardiac surgery adipose tissue samples will be collected. In
more details subcutaneous adipose tissue will be collected from the site of sternum
incision; pericardial adipose tissue will be collected from the site close to right
ventricle; and femoral adipose tissue will be collected from the area of saphenous vein
harvesting (when available). Adipose tissue samples obtained during surgery will be cultured
ex-vivo using a standard adipose tissue protocol.

Biochemical and inflammatory markers: Apart from the common laboratory screening tests
(whole blood count, AST, ALT, γGT, ALP, Urea, Creatinine, glucose, total cholesterol,
triglycerides, LDL, HDL, Na+, K+, Ca2+, CRP), we will determine additional proinflammatory
and prothrombotic biomarkers in patients' plasma. More specifically, using enzyme-linked
immunosorbent assay (ELISA) we will quantify interleukin-6 and other adipokines both in
patients plasma and adipose tissue cultures supernatants. Using high precision liquid
chromatography (HPLC) we will quantify biopterin plasma and vascular levels
(tetrahydrobiopterin, dihydrobiopterin and total biopterins).Studies have shown that the
abovementioned markers may have a prognostic value in high cardiovascular risk patients.

Statistical Analysis: Statistical analysis of results will be done separately according to
the clinical group studied. Therefore there will be separate statistical analysis for
ischemic heart failure patients group (arm A) and for the patients undergoing cardiac
surgery (arm B). Especially for arm B we will compare reactive oxygen species generation
from vascular wall and myocardium between patients randomized to placebo or atorvastatin
40mg/day.

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Medical and Biotech [MESH] Definitions

Coronary Artery Bypass

Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion.

Internal Mammary-coronary Artery Anastomosis

Direct myocardial revascularization in which the internal mammary artery is anastomosed to the right coronary artery, circumflex artery, or anterior descending coronary artery. The internal mammary artery is the most frequent choice, especially for a single graft, for coronary artery bypass surgery.

Coronary-subclavian Steal Syndrome

A complication of INTERNAL MAMMARY-CORONARY ARTERY ANASTOMOSIS whereby an occlusion or stenosis of the proximal SUBCLAVIAN ARTERY causes a reversal of the blood flow away from the CORONARY CIRCULATION, through the grafted INTERNAL MAMMARY ARTERY (internal thoracic artery), and back to the distal subclavian distribution.

Bland White Garland Syndrome

A congenital coronary vessel anomaly in which the left main CORONARY ARTERY originates from the PULMONARY ARTERY instead of from AORTA. The congenital heart defect typically results in coronary artery FISTULA; LEFT-SIDED HEART FAILURE and MITRAL VALVE INSUFFICIENCY during the first months of life.

Coronary Artery Disease

Pathological processes of CORONARY ARTERIES that may derive from a congenital abnormality, atherosclerotic, or non-atherosclerotic cause.

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